Differential Diagnosis in Neurology

10.5. Inherited Peripheral Neuropathies

The history and physical examination of patients with hereditary neuropathies provides a very good chance for a correct clinical diagnosis that is later confirmed with EMG, laboratory and genetic testing.

Patients have specific dysmorphic features. Pes cavus, high arches, intrinsic foot muscle atrophy, hammer toes and a fore shortened foot is most common. Distal 1/3 of quadriceps atrophy, anterior compartment wasting and high insertion of the gastrocnemius and soleus muscles lead to thin ankles. The forearm flexor muscle also inserts too proximally which lead s to thin wrists. Patients often have kyphoscoliosis. They may have associated enlarged nerves, (ulnar, peroneal supraclavicular) foot ulceration, hearing loss, vocal cord and diaphragmatic weakness and cardiomyopathy. Isolated muscles may be atrophied. Patients often are not aware of sensory deficits, but have noted inability to stand in one spot and aching of their lower legs with exercise. They have suffered frequent sprained ankles. Poor gym performance with clumsiness and slight tremor of the upper extremities may be noted. AD, AR and sex linked hereditary is noted. Sporadic mutations may be confused with AR transmission. Unusual susceptibility to pressure at the entrance areas of the nerve to the extremities may be noted with reversible pressure palsies. Gradual and insidious distal weakness of the lower extremities with anterior compartment atrophy becomes apparent. Over time, asymmetric spasticity, optic atrophy and retinitis pigmentosa identify other hereditary neuropathies. Patients have no positive sensory symptoms with time which is prominent in acquired neuropathy.

Weakness and atrophy is noted in hand muscles Classification has been accomplished with EMG, genetic and clinical categories that are now generally established.

Classification of Hereditary Sensory Motor Neuropathies

• HSMN – I (demyelinating; Charcot Marie Tooth)
• HSMN – II (axonal; CMT-2)
• HSMN – III (Déjérine–Sottas Disease; CMT-3)
• HSMN – IV (demyelinating; Refsum's Disease)
• HSMN – V (peripheral neuropathy and spastic paraplegia)
• HSMN – VI (peripheral neuropathy and optic atrophy)
• HSMN – VII (peripheral neuropathy and retinitis pigmentosa)

Charcot–Marie–Tooth Neuropathy Type I (CMT IA)

• General features:
  • Epidemiology: Incidence of 1:4000; 50% of hereditary neuropathies
  • Genetics:
    • AD; duplication of 1.5 mega base DNA on chromosome 17 p 1.2–12
    • Frequently sporadic (defect primarily in spermatogenesis; 10% occur from defect of oogenesis)
    • 500 kilobase Sac II junctional fragment
    • Trisomy patients of duplicated region demonstrate:
      • Mental retardation
      • Pes cavus
      • Micrognathia
      • Low set hypoplastic ears
  • Gene: PMP-22 gene:
    • Encodes a 160 amino acid membrane associated protein localized to compact peripheral nerve myelin
  • Some patients have point mutation of PMP-22 gene
• Clinical presentation:
  • Presents 2nd to 3rd decade, may have delay in motor milestones
  • Pes cavus, atrophy of all muscle below the calf (anterior compartment greater than posterior compartment); wasting distal 1/3 of quadriceps ("Champagne bottle leg")
  • Asymmetric gradual involvement of thenar and hypothenar compartment of the hands; thinning of the distal forearms
  • Motor manifestations predominate; diminished vibration, proprioception and light, touch; cramps are common
  • Absent ankle and knee reflexes; depressed upper extremity reflexes
  • Enlarged nerves; brachial plexus; supraclavicular, ulnar, peroneal
  • Insidiously progressive
  • Patients remain ambulatory
  • Kyphoscoliosis
• EMG:
  • Severely slowed motor and sensory NCV (<40 meters/second)
• Pathology:
  • "onion bulb" formation

Charcot–Marie–Tooth 1B (CMT 1B)

• General features:
  • Epidemiology:
    • 1:80000 incidence; 5% of hereditary demyelinating neuropathies
  • Genetics:
    • AD; linked to the Duffy (FY) locus on long arm of chromosome 1 q
    • Chromosome 1 q 22–q 23
    • Gene: human myelin protein zero-PO gene
      • Immunoglobulin gene superfamily of adhesive molecules
      • Encoded protein localizes to compact portion of compact myelin
      • Point mutations
• Clinical presentation:
  • Slowly progresses; loss of distal strength in the extremities; asymmetric gradual loss of hand strength
  • Proprioception, vibration and touch sensibility loss greater than temperature and pain
  • Occasional weakness of isolated proximal muscles (trapezius; deltoid)
  • Pes cavus and atrophy similar to CMT 1A
  • Intention tremor of the upper extremity
• EMG:
  • Slowed motor and sensory NCV (<40 m/sec)
• Pathology:
  • "onion bulb formation"
  • Hypertrophic demyelinating neuropathy

Charcot–Marie Tooth Disease Type 1C-CMTIC

• General features:
  • Genetics:
    • AD; not linked to 17p or chromosome 1q
• Clinical presentation:
  • Slowly progressive distal motor sensory neuropathy
  • Kinesthetic sensory loss
• EMG:
  • Slowed motor and sensory NCV's
• Pathology:
  • "onion bulb formation"
  • Hypertrophic demyelinating neuropathy

Charcot–Marie Tooth-1D

• General features:
  • Genetics:
    • Linkage to chromosome 10 q 21–q22
    • Gene: EGR-2 (early growth response-2 gene or Krox-2; point mutation in the gene

HSMN Type II (CMT 2 A)

• General features:
  • Epidemiology: Approximately 20% of inherited neuropathies
  • Genetics:
    • Linkage to chromosome 1p35–p36
    • Genetic heterogeneity
• Clinical presentation:
  • Later onset than CMT1
  • Non palpable nerves
  • Less intrinsic hand muscle involvement
  • Pes cavus intrinsic foot muscle atrophy
  • Occasional isolated proximal muscle atrophy (asymmetric)
  • Note distal weakness predominates over large fiber sensory loss
  • Loss of ankle and knee jerks; with time areflexia
• EMG:
  • Normal motor and sensory conduction velocities
• Pathology:
  • Axonal neuropathy

CMT-2B

• General features:
  • Genetics; linkage to chromosome 3q13–q22; AD
• Clinical presentation:
  • Sensory greater than motor signs and symptoms
  • Ulcerations of the feet
  • Amputation of digits
• EMG:
  • Normal motor and sensory conduction velocities
• Pathology:
  • Axonal neuropathy

CMT-2C

• General features:
  • Genetics:
    • Linkage and gene unknown
    • AD
• Clinical presentation:
  • Distal to proximal motor much greater than large fiber modality sensory loss
  • Diaphragm involvement
  • Vocal cord involvement
  • Insidiously progressive
• EMG:
  • Normal motor and sensory conduction velocities
• Pathology:
  • Axonal neuropathy

CMT-2D

• General features:
  • Genetics:
    • Linkage to 7p14
    • Gene has not been determined possibly allelic to distal SMA gene
• Clinical presentation:
  • Primarily a motor neuropathy
  • Slowly progressive
• EMG:
  • Normal motor NCVs
• Pathology:
  • Axonal neuropathy

CMT-2E

• General features:
  • Genetics:
    • Linkage to chromosome 8q21
    • NF-L gene (neurofilament light chain); point mutation

X-linked Charcot–Marie–Tooth Neuropathy

• General features:
  • Epidemiology:
    • Second most common form of CMT
    • Incidence: 1:20,000; 10–15% of hereditary neuropathies
  • Genetics:
    • Linkage to the proximal long arm of the X-chromosome (Xq13–q21)
    • Gene: GJB
      • Encodes a component of gap junctions connexin 32 ( Cx32)
      • Point mutation
      • Cx32 forms gap functions between myelin layers of Schwann cells also junction between oligodendrocytes and astrocytes in the central nervous system
• Clinical presentation:
  • Absence of male to male transmission
  • Earlier age of onset and faster rate of progression than CMT 1 and 2
  • More severe phenotype in men
  • Similar pes cavus and distal lower extremity atrophy
  • Motor greater than sensory large fiber modality neuropathy
  • Hearing loss is seen
  • Gradually progressive
• EMG:
  • Slower intermediate motor and sensory NCVs
• Pathology:
  • Demyelinating neuropathy

The Central Nervous System Phenotype of X-Linked Charcot–Marie–Tooth Disease

• General features:
  • Genetics:
    • GJB1 mutations with acute disseminated encephalomyelitis attacks (ADEM):
• Clinical presentations:
  • ADEM (acute disseminated encephalomyelitis attacks)
  • Dysphagia; dysarthria; expressive aphasia, paresis, cerebellar dysfunction and cranial neuropathy
  • Sudden onset or progressive over days; fluctuating; clusters of attacks over several weeks
  • Recover completely
  • Attacks provoked by travel, stress, fever; infection
• MRI evaluations of patients with CMT X-linked with ADEM attacks:
  • Increased T2 weighted signal; no enhancement:
    • Posterior centrum semiovale
    • Splenium of the corpus callosum
    • Middle cerebellar peduncle
    • Spare subcortical μ fibers
    • Persist for months
  • White matter signal abnormalities may occur without ADEM-like attacks
  • GJB1 mutations may be associated with slowed central conduction:
    • BAER (abnormal)
    • VEP (abnormal)
    • Central motor evoked potentials (slowed)
  • Subclinical central involvement may occur without MRI abnormality
  • Putative mechanism:
    • Disruption of gap junction between oligodendrocytes and astrocytes

Hereditary Motor Sensory Neuropathy Type III (Déjérine–Sottas)

• General features:
  • Genetics:
    • Associated with point mutations in the PO or the PMP-22 genes
    • All mutations noted in the heterozygous state
    • Possibly AR form
    • Point mutation in the PO gene causes congenital hypomyelinating neuropathy (CHN) the severest form Déjérine–Sottas (DSD)
• Clinical presentation:
  • Starts in the first decade
  • Hypotonia in infancy; delay in motor milestones
  • Arms and legs affected simultaneously
  • Distal motor weakness greater than large fiber neuropathy
  • Enlarged nerves; may cause radicular or cauda compression in adulthood; enlarged nerves are seen on myelopathy or by MRI:
    • R/o neurofibromatosis
    • R/o drop metastasis
  • Short statures nystagmus, hearing loss, facial weakness, pupillary dysfunction
  • Hearing loss
  • Facial weakness
  • Pupillary dysfunction
  • Nystagmus
  • Pes cavus and similar extremity dysmorphism or other
  • Claw hand and club foot deformities
  • May not walk
  • Severe kinesthetic deficits with pseudoglottis
• EMG:
  • Severely slowed motor and sensory NCVs <10 m/sec
• Pathology:
  • Demyelinating neuropathy

Charcot–Marie–Tooth 4A (CMT 4A)

• General features:
  • Genetics:
    • Chromosome 8q13–q21; AR
    • Rare Tunisian families with sensorimotor neuropathy that are AR
• Clinical presentation:
  • Severe sensory motor neuropathy
  • Primarily large fiber sensory modalities involved
  • Slowly progressive
• EMG:
  • Slowed motor and sensory NCV
• Pathology:
  • Demyelinating neuropathy

Charcot–Maria–Tooth Type 4B

• General features:
  • Genetics:
    • Chromosome 11q22
    • Mutations in the myotubular related protein – 2 gene
• Clinical presentation:
  • Childhood mean age of onset is 34 months
  • Progressive distal greater than proximal muscle weakness and atrophy
  • Pes equina varus develops in childhood
  • Normal intellectual function
  • Adult patients:
    • Mean age of onset is 27
    • Wheelchair bound; death 4–5th decade
    • Distal and proximal weakness
    • Large fiber sensory modality loss
    • Abnormally delayed intra peak I–III latencies (BAER)
• EMG:
  • Motor nerve conduction velocities 15 to 17 m/sec in the upper limbs of the youngest patients
  • Undetectable MNCV in adult patients
• Pathology:
  • Irregularly redundant loops and folding of myelin

CMT4C

• General features:
  • Genetics: (CMT4C)
    • AR
    • Chromosome 5q22–23
    • Algerian families
    • Six non related European families
• Clinical presentation:
  • Sensorimotor neuropathy
  • European families; early onset with rapidly progressive scoliosis
  • Insidiously progressive course
• EMG:
  • Slowed motor and sensory NCV
• Pathology:
  • Demyelinative neuropathy

Rare CMT Phenotypes

Autosomal Recessive Charcot–Marie–Tooth Disease with Deafness

• General features:
  • Genetics:
    • AR
    • Chromosome 8q24
    • Bulgarian Gypsy families
• Clinical presentation:
  • Motor and sensory neuropathy
  • Deafness
  • Gradually progressive
• EMG:
  • Slow motor and sensory neuropathy
• Pathology:
  • Demyelinating neuropathy

X-Linked Axonal Neuropathy with Deafness and Mental Retardation

• General features:
  • Genetics: Xq24–26
• Clinical presentation:
  • Severe motor and sensory neuropathy
  • Deafness
  • Mental retardation
  • Gradually progressive deficits
• EMG:
  • Normal NCV
• Pathology:
  • Axonal

Autosomal Recessive Charcot–Marie–Tooth Disease

• General features:
  • Genetics:
    • Unmapped
    • Several families reported
• Clinical presentation:
  • Motor and sensory neuropathy
  • Gradually progressive
• EMG:
  • Normal motor nerve conduction velocities
• Pathology:
  • Axonal

Hereditary Sensory Neuropathy (HSN)

• General features:
  • Genetics:
    • AD
    • Chromosome 9q22
• Clinical presentation:
  • Loss of temperature and pain sensation
  • Ulceration and osteomyelitis of the digits
  • Subtle distal extremity weakness
  • Gradually progressive
• EMG:
  • Normal sensory conduction velocities
• Pathology:
  • Axonal neuropathy

Hereditary Motor Neuropathy

• General features:
  • Genetics: AD
  • Linked to chromosome 12q24
• Clinical presentation:
  • Motor neuropathy solely
  • Distal predominant
  • Slowly progressive
• EMG:
  • Normal conduction velocities
• Pathology:
  • Axonal neuropathy

Congenital Hypomyelinating Neuropathy (CHN)

• General features:
  • Genetics:
    • Point mutation in the PO gene; 1 q 22–23
    • Point mutation in EGR-2 gene; 10q21–q22
• Clinical presentation:
  • Severe motor sensory neuropathy
  • Most patients have normal cognition
  • Patients with less encephalopathic and axonal neuropathy have been reported
  • Severe deficits from birth
• EMG:
  • Very slow motor and sensory NCVs
• Pathology:
  • Axonal and demyelinating

Hereditary Neuropathy with Liability to Pressure Palsies

• General features:
  • Genetics:
    • Chromosome 17p11 2–12; deletion of 1.5 mb of the same region associated with CMT1A duplication which includes the PMP-22 gene
    • The genetic reciprocal of the duplicated DNA of CMT 1A
• Clinical presentation:
  • Incidence of 1:10,000 people
  • Starts in adolescence
  • Neuropathy of major nerves at the site of entrapment (cubital and carpal tunnel; peroneal nerve at the fibular head; tarsal tunnel; Arcade of Frohse; ligament of Struthers; brachial plexus costoclavicular and scalene sites)
  • Recurrent painless brachial plexopathy; females > males
  • Recurrent pain less mono neuropathies (often without full recovery)
  • Numbness, weakness and atrophy after mild trauma or compression
  • Some patients have progressive polyneuropathy than resembles CMT with distal weakness, sensory loss and absent ankle jerks
  • Rare patients are asymptomatic; examination often reveals pes cavus and decreased reflexes
  • Pure sensory nerve involvement occurs
  • Facial nerve involvement occurs rarely
  • A few patients present in childhood or after age 50; men present at an earlier age than women
  • Phenotypic heterogeneity occurs within families
• EMG:
  • Electrophysiologic evidence of involvement of symptomatic nerves; conduction block in areas of injury; slowed motor and sensory NCVs:
    • Non HNPP patients with painless mononeuropathy suffer peroneal palsy or ulnar compression following recent weight loss; specific postures crossing the legs, or leaning on the elbow, and have normal electrophysiologic studies of uninvolved nerves
• Pathology:
  • Segmental demyelination
  • Tomaculous or "sausage-like" myelin formations of affected nerves

Hereditary Motor Sensory Neuropathy Type IV-Refsum's Disease (HSMN IV)

• General features:
  • Genetics:
    • AR; gene on chromosome 10; Scandinavian primarily
    • Encode: peroxisomal enzyme phytanoyl-CoA hydrolase (PAHX)
    • Catalyzes the oxidation of phytanic acid to hydroxy phytanic acid
• Clinical presentation:
  • Present between 10–30 years of age
  • Earliest symptom night blindness due to retinitis pigmentosa
  • Sensorimotor peripheral neuropathy
  • Enlarged nerves
  • Intermittent neuropathy (early in the course) due to:
    • Increased phytanic acid
    • Infections
  • VIIIth nerve dysfunction
  • Cataracts
  • Anosmic
  • Pupillary dysfunction
  • Ichthyosis
  • Skeletal deformities
  • Scoliosis and short stature
  • Cardiomyopathy (dilatate)
• Laboratory:
  • Increased CSF protein without pleocytosis
  • Increased phytanic acid levels in serum
• EMG:
  • Slowed motor and sensory NCVs
• Pathology:
  • Segmental demyelination
  • Depletion of myelinated fibers
  • Onion bulb formation
  • Osmophilic and crystalline bodies in Schwann cells

Infantile Refsum Disease

• General features:
  • Genetics:
    • Defective PEX genes (Peroxin)
    • Defective peroxisomal biogenesis
• Clinical presentation:
  • Mental retardation
  • Sensorineural deafness
  • Retinitis pigmentosa
  • Hepatomegaly
  • Sensorimotor neuropathy
• EMG:
  • Moderately reduced motor NCV
• Pathology:
  • Demyelination
  • Loss of myelinated fibers without hypertrophic abnormalities

Hereditary Motor Sensory Neuropathy Type V Associated with Spastic Paraplegia

• General features:
  • Genetics:
    • AD
    • AR (Troyer Syndrome)
• Clinical presentation:
  • Begins in the second decade with spasticity
  • Insidiously progressive; may become wheelchair bound in the 4th decade
  • Early stage of the disease toe walking; later a scissors gait
  • No sensory abnormality
  • Severely hyperactive reflexes in the lower extremities; bilateral Babinski signs
• EMG:
  • Normal motor nerve conduction velocities in the upper extremities
  • Loss or normal or slightly reduced MNCs in the lower extremities
  • Decreased sural nerve amplitude or its absence has been noted
  • Denervation of the distal leg and foot muscles

Hereditary Motor Sensory Neuropathy with Optic Atrophy Type VI

• General features:
  • Genetics: Sex linked AR
• Clinical presentation:
  • Peroneal muscle atrophy; later hands are affected
  • Pes cavus
  • Lancinating pain in the extremities
  • Loss of visual acuity; may progress to blindness
  • Tendon reflexes normal or decreased
  • Some kinships anticipation is noted
  • One kinship with hypertrophic neuropathy

Hereditary Motor Sensory Neuropathy Type VII with Retinitis Pigmentosa

• General features:
  • Genetics: AR
• Clinical presentation:
  • Distal limb weakness
  • Cutaneous sensation normal; decreased lower extremity fibration sensibility
  • Absent ankle jerks
  • Retinitis pigmentosa

Not Well Characterized Hereditary Motor Sensory Neuropathies

• Associated with spinocerebellar degeneration including olivopontocerebellar degeneration (OPCA)
• Cerebellar degeneration with external ophthalmoplegia (mitochondrial disorders)
• Associated with mental retardation, distal atrophy and muscle weakness
• Association of peroneal muscle atrophy, ataxia and myopathy

Associated Congenital Features and Hereditary Sensory Motor Neuropathy

• Shallow acetabulum with subluxation of the hip
• Scoliosis
• Tall asthenic appearance; long arms
• Long second toe; syndactyly of the second and third toes
• Linear zone of cutaneous depigmentation

Hereditary Motor Sensory Neuropathy X1 (CMTX1)

• General features:
  • Genetics: localized to q13–q21:
    • No male to male transmission
    • Males affected more severely than females
    • If father affected:
      • All daughters are affected, but sons are unaffected
    • If mother is affected:
      • 1/2 of her daughters and sons are affected
• Clinical presentation:
  • Males affected more severely than females
  • Gradually progressive
  • Motor greater than sensory symptoms
• EMG:
  • Slightly slowed motor NCV
• Pathology:
  • Axonal neuropathy

Hereditary Motor Sensory Neuropathy X2 (CMTX2)

• General features:
  • Genetics:
    • X-linked recessive
    • Carrier status of 1/2 of the daughter
    • Heterozygous mother
    • None of the sons of the affected father are affected; all daughters are carriers
• Clinical presentation:
  • Peroneal muscular atrophy
  • Deafness
  • Mental retardation
• Hereditary Sensory Autonomic Neuropathy
  • Dominantly Inherited Sensory Neuropathy – HSANI (pp)
  • Recessive Inherited Sensory Neuropathy – HSANII (pp)
  • Riley–Day Syndrome – HSAN III (pp)
  • Congenital Sensory Neuropathy with Anhidrosis – HSAN IV (pp)
  • HSAN V (pp)

Variants of HSAN

• Children with non-progressive neuropathy and dysautonomia; total loss of myelinated fibers in peripheral nerve
• AR sensory neuropathy with hereditary spastic paraplegia
• AD sensory neuropathy with hereditary spastic paraplegia

Differential Diagnosis of Hereditary Neuropathies

The clinical differential diagnosis of the hereditary neuropathies rests on determination of their genetic basis and specific seminal aspects of the physical examination. Historical points such as age of onset, pattern of involvement, modality of predominant sensory loss, progression versus intermittency and specific symptoms are critical.

The differential diagnosis of CMT1 and CMT2 includes specific inherited, metabolic and genetic neuropathies. CMT1 demonstrates enlarged nerves with onset in legs and later asymmetric involvement of the hands. Nerve motor and sensory conduction velocities are slowed. CMT-2 has normal sized nerves and a tendency to involve asymmetric proximal muscles. CMT-2B has marked large fiber modality loss with foot ulcer and occasional severe pseudoathetosis. The hallmark of CMT-3 or Dejerine Sottas Disease (HSMN III) is enlarged nerves with early involvement of both hands and legs. There are other dysmorphisms such as nystagmus, pupillary involvement and short stature. The nerves are large enough that on occasion cause cauda equina compression. CMT-2C is characterized by diaphragmatic weakness and vocal cord paralysis. X-linked Charcot–Marie–Tooth neuropathy is suspected by the absence of male to male transmission and early age of onset with hearing loss. The spinocerebellar atrophies with CMT have dramatic cerebellar dysfunction, dysarthria and nystagmus that are not seen with CMT. The HSMN V–VII are suggested by severe spasticity, brainstem forms of nystagmus retinitis pigmentosa, optic atrophy and dementia. Refsum's Disease (HSMN IV) is suspected from the combination of cataracts retinitis pigmentosa dementia and hearing loss. It may also be intermittent depending on the level of serum phytanic acid. The outstanding feature of HNNP is the occurrence of different mononeuropathies from minimal compression or trauma with usual recovery. The brachial plexus is often involved painlessly. The differential loss of small fiber function, insensitivity to pain and autonomic dysfunction separate the HSAN I–IV from CMT. The distal forms of SMA and ALS in adolescents may present with foot drop and distal atrophy, but have no sensory loss. Joint contracture which may be seen in Emery Dreifuss muscular dystrophy, fiber type disproportion, FSHD and distal SMA are not seen in CMT. The pes cavus of different anterior horn cell disease is less symmetric and the gastrocnemius and soleus insertions are less proximal. The Fazio Lande form of adolescent ALS progresses too rapidly for any form of CMT. Acquired demyelinating form of CIDP may affect the same distribution of muscles as CMT, but is asymmetric, often proceeded by unilateral perioral numbness, has more generalized areflexia and no congenital foot stigmata. Enlarged nerves noted in CMT and DSD may be seen in acquired autoimmune neuropathies, but not to the same degree. There is more often peripheral VIIth nerve involvement with CIDP and characteristically more VIIIth nerve involvement in CMT-X. HNPP is easily differentiated from hereditary neurologic amyotrophy which presents with painful episodes of brachial plexopathy. A subset of these patients demonstrated abnormalities of the nasal bridge, hypotelorism and up slanting palpebral fissures. This entity may be difficult to differentiate from chronic regional pain syndrome (CRPS II). In this entity, the movement disorder of decreased initiation of movement.

HSMN V, VI and VII are diagnosed by the accompanying spastic paraparesis, optic atrophy and retinitis pigmentosa. Multifocal motor neuropathy with conduction block is frequently more commonly seen in the upper extremity and may mimic HNPP, but is unassociated with sensory loss and is progressive rather than remittent.

The EMG is the most helpful component of the laboratory evaluation in the differential diagnosis of CMT. The clinical evaluation with a specific diagnosis focuses the EMG study. The evaluation immediately separates the neuropathy into primarily an axonal or demyelinating. It may demonstrate anterior horn cell or myopathic disorders that are unsuspected. The sensory neuron action potentials (SNAPs) are normal in these disorders, but are abnormal in various peripheral neuropathies. Inherited demyelinative neuropathies have uniformly slowed conduction velocities with prolonged distal latencies whereas acquired demyelinative neuropathies have asymmetric slowed conduction blocks at new entrapment sites and are often prominent in the upper extremities. EDX has many specific finding for different inherited neuropathies.

CSF evaluation demonstrates very high protein in Refsum's Disease (100–700 mg /dL ). In general, 50% of CMT patients have elevated protein without pleocytosis. This evaluation is helpful when autoimmune acquired neuropathies are suspected. Genetic testing and EMG evaluation have limited the necessity for nerve biopsy in the differential diagnosis of inherited neuropathies.

Inherited Neuropathies Associated with Specific Metabolic Defects

• Familial Amyloid Polyneuropathy:
  • General characteristics:
    • AD
    • Secondary to the deposition of a fibrillar protein with a beta-pleated structure in the extra-cellular space
    • There are three types of peripheral nerve amyloid:
      • Primary amyloid light chain (acquired)
      • B2-microglobulin-related amyloidosis (acquired/localized)
      • Familial amyloid polyneuropathy (FAP)
    • Three hereditary subgroups of FAP protein are deposited:
      • determined by constituent fibrillar protein deposited
      • Most common is transthyretin (TTR-related met 30, prealbumin)
      • Apolipoprotein A-1-related FAP
      • Gelsolin-related FAP

Transthyretin Related FAP

• General features:
  • Genetics:
    • Point mutation of TTR gene (methionine 30) Met 30; chromosome, 1.8q 1/12–q 12.1
    • AD
• Clinical presentation:
  • Earliest presentation is in the legs with a painful small fiber neuropathy; early loss of pain and temperature modalities; all sensory modalities are involved with time
  • Ulcers, osteomyelitis and Charcot joints in the extremities
  • Wasting, weakness and areflexia
  • Met 30 mutation has a long interval to arm involvement
  • TTR Ser 84; TTR; His 58 mutations present with arm involvement (CTS common to both)
  • Autonomic involvement is severe in all mutations:
    • May appear early
    • Sexual, urinary and gastric dysfunction
    • Large pupils; light near association
    • Abnormal Valsalva response
    • Fixed heart rate
    • Severe postural hypotension
    • Vitreus amyloid deposits (primary uveal veil) most common in Swedish patients
    • Cardiac involvement:
      • Restrictive or hypertrophic cardiomyopathy
      • Conduction block (heart block)
      • Q waves; T-wave repolarization abnormalities
      • Feature of Ala 60 mutation
      • Arrhythmia
    • Renal involvement
    • Bone infiltration
  • CNS involvement in TTR (FAP now known as Oculoleptomeningeal Amyloidosis OLMA):
    • Occurs with Met 30; Val 30; Glycol, Pro 12 mutations:
      • Vitreous opacities
      • Stroke
      • Subarachnoid hemorrhage
      • Ataxia
      • Seizures
      • Spasticity
      • Hydrocephalus
      • Fluctuating consciousness
      • Focal neurologic signs
      • Dementia
      • Peripheral neuropathy with cardiac involvement
• EMG:
  • Axonal polyneuropathy; long standing patients demonstrate denervation
• Pathology:
  • Amyloid is detected by biopsy of rectum or nerve:
    • Polarizing filters demonstrate apple green birefringence
    • Most commonly located around blood vessels; patchy distribution
    • Extensive amyloid deposition determined by 123 iodine-labeled serum amyloid protein
  • Genetic diagnosis:
    • In heterozygotes with TTR-related FAP:
      • Both normal and variant TTR is in the serum
      • Detected by enzyme-linked immuno absorbent assay
      • Radioimmune assay

Differential Diagnosis of Amyloid Neuropathy

Primarily that of a small fiber neuropathy: the prominent vitreous abnormality is a sentinel differential point. The upper extremity involvement in some patients with TTR (met 84 and His 58) separates these from the small fiber neuropathies that are primarily distal symmetrical and present with early burning feet. The severe ulcers, painless foot ulceration and Charcot joints may be seen with CMT-2B although upper extremity pseudoathetosis and pes cavus differentiated this from TTR Met 30 FAP. Hereditary sensory autonomic neuropathy (HSAN) may have similar small fiber extremity abnormalities, but does not have cardiac or vitreous involvement. The toxic neuropathies do not have cardiac involvement, but may suffer optic nerve demyelination. Orange tonsils distinguish Tangiers's Disease and angiokeratosis, anhidrosis stroke and renal failure are characteristic of Fabry's Disease. Fabry's Disease patients suffer more lancinating pain and acroparesthesias whereas TTR Met 30 and Leprosy patients have the consequence of diminished pain sensibility. Retinopathy, nephropathy and burning feet or more commonly generalized sensorimotor neuropathy suggest diabetes. Disc disease of the thoracic spine suggests diabetes, amyloid neuropathy, relapsing polychondritis or ochronosis (many thoracic discs are calcified). Amyloid, leprosy, syphilis, diabetes and syrinx all cause Charcot joints. Severe autonomic symptomatology out of proportion to other aspects of small fiber disease suggests primary-light chain amyloidosis. Small fiber neuropathy, vitreous opacities, restrictive or hypertrophic cardiomyopathy and autonomic neuropathy make the diagnosis of TTR-Met 30 amyloid.

Gelsolin-Related Familial Amyloid Polyneuropathy

• General features:
  • Genetics:
    • Gelsolin gene; point mutation
    • Abnormal fragment of the plasma protein Gelsolin is deposited
• Clinical presentation:
  • Begins in the fourth decade
  • Corneal lattice dystrophy
  • VIIth nerve neuropathy (upper forehead weakness)
  • Facial skin thickened early; then lax with time
  • Mild, sensory and autonomic neuropathy

Apolipolipoprotein A-1-Related Familial Amyloid Polyneuropathy

• General features:
  • Genetics: deposition of a variant of apolipoprotein A-1
• Clinical presentation:
  • Similar to that of TTR Met 30
  • Higher incidence of renal disease
  • Gastric ulcers are prominent

Differential Diagnosis by Ethnicity of FAP

Clinical Syndromes by Ethnicity

• Portuguese patients:
  • Early onset; lower leg involvement
  • More affected in men than women
• Swedish patients:
  • Vitreous involvement
  • Later presentation
  • More affected men than women; women present at a later age; earlier onset if the disease is inherited from the mother
• French patients:
  • Present late
  • Shorter disease duration
• Met 30 mutation patients:
  • Sporadic patients described
  • Marked variability in time of onset and clinical symptomatology

Porphyria

• General features:
  • 4 types of porphyria with neurologic sequelae:
    • Acute intermittent (AIP)
    • Variegate porphyria
    • Hereditary coproporphyria (HCP)
    • Amino levulinic acid dehydrase deficiency
  • Defects in these enzymes cause a slight reduction in heme synthesis and specific elevated porphyrin precursors in the serum and urine
  • Only the hepatic porphyrias are associated with neurologic symptoms

Acute Intermittent Porphyria

• General features:
  • Genetics:
    • AD; incomplete penetrance; 90% of patients are latent
    • Short arm of chromosome 11; two RNAs produced by alternative transcription and splicing; one is erythrocyte specific
    • Partial deficiency of porphobilinogen deaminase (PBG)
    • Insertions; deletions; single base substitutions in the gene
• Clinical presentation:
  • Neurological complications of all porphyrias are similar
  • Most attacks are provoked by any drugs that induce the hepatic microsomal cytochrome 450 system:
    • Chlorpromazine, demerol; valium, gabapentin are safe
  • Starvation, alcohol, stress, hormonal changes precipitate attacks
  • Some patients have chronic abdominal pain and discomfort without overt attacks; others may suffer patchy sensory or radicular pain without overt attacks.
  • Acute attacks five times more common in women than men
  • Abdominal pain is the most common symptom of an acute attack:
    • Soft abdomen; X-ray demonstrates dilated loops of bowel
    • Accompanied by nausea, vomiting and constipation
  • Agitation, nightmares, psychosis are common
  • Coma supervenes during severe attacks
  • Inappropriate ADH with very low serum sodium 110–120 mEq occur
  • Generalized tonic clonic seizures; between attacks some patients suffer occipital seizures
  • Primarily an axonal motor neuropathy
  • Ascending GBS syndrome occurs; ankle reflexes may be spared
  • Severe wasting of muscle occurs during attacks; often recovers fully
  • Rare ophthalmoplegia and cranial nerve involvement
  • Autonomic dysregulation with tachycardia, hypo or hypertension, hyperhidrosis and pupillary dilatation with light near dissociation
  • Repeated attacks may lead to hypertension and chronic renal failure
• Laboratory evaluation:
  • Slight anemia (Hb-2–12 grams/dL )
  • Minimal elevation of hepatic enzymes
  • High cholesterol in some patients
  • During acute attacks elevation in serum and urine:
    • Porphobilinogen
    • Delta amino levulinic acid
  • Decreased PBG deaminase in RBC

Variegate Porphyria

• General features:
  • Genetics:
    • AD; 3/1000 people in South Africa
    • Gene for protoporphyrinogen oxidase (PPG) is on chromosome
• Clinical presentation:
  • Same neurological presentation as AIP
  • Skin rash may be the only manifestation
• Laboratory evaluation:
  • During acute attacks elevations of:
    • PBG and coproporphyrin, delta amino levulinic acid (ALA)
    • PPG oxidase activity in leukocytes is decreased

Hereditary Coproporphyria (HCP)

• General features:
  • Genetics:
    • AD; Chromosome 3
    • Enzyme defect is coproporphyrinogen oxidase
• Clinical presentation:
  • Same as AIP
  • Skin blisters occur during the attacks
• Laboratory:
  • Elevation of urinary and fecal coproporphyrins
  • Elevation of ALA, PBG and uroporphyrins
  • Decreased CPG oxidase in leukocytes

ALA Dehydrase Deficiency

• General features:
  • Genetics:
    • AR (rare); chromosome 9 is location of ALA dehydrase gene
    • Homozygous deficiency of ALA dehydrase
• Clinical presentation:
  • Similar to AIP
• Laboratory:
  • Elevations of ALA; minimally elevated urinary PBG
  • Decreased ALA dehydrase activity in serum

Pathology of Porphyrias

• Axonal peripheral neuropathy
• Patchy demyelination

Differential Diagnosis

• Heavy metal intoxications particularly lead may cause abdominal pain
  • CNS symptoms (most often in children) and an axonal neuropathy.
  • Pb axonal neuropathy often occurs in the arm that is used (painter's radial palsy)
• Arsenic causes nausea and vomiting acutely with later hyperkeratosis of soles and palms; painful sensory neuropathy
• Thallium toxicity acutely may present with severe abdominal pain and cardiac manifestations an axonal neuropathy with hair loss.
• Heavy metal intoxication is associated with elevated urinary coproporphyrins.
• Acute axonal GBS may resemble AIP.
  • There is no abdominal pain (GBS), ankle reflexes may be maintained in AIP and both may have severe autonomic dysregulation.